In Project 2 of the current Program Project, the investigators have previously proposed to identify and characterize the underlying molecular defect in two multiple malformation syndromes leading to stillbirth or perinatal lethality: Meckel Syndrome and Hydrolethalus. These conditions are characterized by craniofacial/limb abnormalities, brain and cardiac defects, and dysplasia of parenchymal organs. Since these two severe malformation syndromes share several hallmark symptoms, it is probable that the molecular defect in them will guide us to partially interacting metabolic/developmental pathways. By combining genome-wide mapping, cybercloning, comparative human/mouse mapping studies in collaboration with Dr. Monica Justice in Project 3, and direct mutation analysis, the investigators proposed to identify the specific gene defects. Then by combining functional genomic studies of Drosophila and mouse models with tissue array studies, they will dissect the underlying developmental pathway. Because progress on these fronts has been so rapid with the identification of the genes for both conditions and with functional studies well in progress, the researchers propose to expand on the application of their unique resource of the Finnish population and Birth Defects Registry. In this supplemental application, they propose to study a third early malformation syndrome: LCCS. This syndrome adds to the spectrum of developmental defects under study since it has additional pathonogmonic features including anterior horn motor neuron degeneration. It serves as a model for severe forms of neurogenic arthrogryposis. The analogous experimental approaches as proposed in the current project with Meckel syndrome and Hydrolethalus will be applied. Together, these studies should identify central developmental pathways that when dysregulated by genetic mutation will cause birth defects affecting the craniofacies, limb, brain, and spinal cord. [unreadable] [unreadable]